Protein kinase inhibitors

ABSTRACT

In one aspect, the invention provides compounds of Formula I 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof. In another aspect, the invention provides methods for treatment of diseases or disorders mediated by a protein kinase, comprising administering a therapeutically effective amount of a compound of this invention.

This application claims priority to U.S. Ser. No. 61/074,754, filed Jun.23, 2008. The entire contents of the aforementioned application areincorporated herein.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of intensive study is protein kinases.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell (see, e.g., G. Hardie et al., TheProtein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.,1995). Protein kinases are thought to have evolved from a commonancestral gene due to the conservation of their structure and catalyticfunction. Almost all kinases contain a similar 250-300 amino acidcatalytic domain. The kinases may be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, lipids etc). Sequence motifs have beenidentified that generally correspond to each of these kinase families(see, e.g., S. K. Hanks et al., FASEB J., 1995, 9, 576-596; Knighton etal., Science 1991, 253, 407-414; Hiles et al., Cell, 1992, 70, 419-429;Kunz et al., Cell, 1993, 73, 585-596; Garcia-Bustos et al., EMBO J.,1994, 13, 2352-2361).

In general, protein kinases mediate intracellular signaling by affectinga phosphoryl transfer from a nucleoside triphosphate to a proteinacceptor that is involved in a signaling pathway. These phosphorylationevents act as molecular on/off switches that can modulate or regulatethe target protein biological function. These phosphorylation events areultimately triggered in response to a variety of extracellular and otherstimuli. Examples of such stimuli include environmental and chemicalstress signals (e.g., shock, heat shock, ultraviolet radiation,bacterial endotoxin, and H₂O₂), cytokines (e.g., interleukin-1 (IL-1)and tumor necrosis factor alpha (TNF-a), and growth factors (e.g.,granulocyte macrophage-colony stimulating factor (GM-CSF), andfibroblast growth factor (FGF)). An extracellular stimulus may affectone or more cellular responses related to cell growth, migration,differentiation, secretion of hormones, activation of transcriptionfactors, muscle contraction, glucose metabolism, control of proteinsynthesis, survival and regulation of the cell cycle.

Many diseases are associated with abnormal cellular responses triggeredby protein kinase-mediated events as described above. These diseasesinclude, but are not limited to, cancer, autoimmune diseases,inflammatory diseases, bone diseases, metabolic diseases, neurologicaland neurodegenerative diseases, cardiovascular diseases, allergies andasthma, Alzheimer's disease and hormone related diseases. Accordingly,there has been a substantial effort in medicinal chemistry to findprotein kinase inhibitors that are effective as therapeutic agents.

The Polo-like kinases (PLKs) belong to a family of serine/threoninekinases that are highly conserved across the species, ranging from yeastto man (reviewed in Lowery D M et al., Oncogene, 2005, 24, 248-259). ThePLKs have multiple roles in cell cycle, including control of entry intoand progression through mitosis.

PLK1 is the best characterized of the PLK family members. PLK1 is widelyexpressed and is most abundant in tissues with a high mitotic index.Protein levels of PLK1 rise and peak in mitosis (see, e.g., R. Hamanakaet al., J. Biol. Chem., 1995, 270, 21086-21091). The reported substratesof PLK1 are all molecules that are known to regulate entry andprogression through mitosis, and include CDC25C, cyclin B, p53, APC,BRCA2 and the proteasome. PLK1 is up-regulated in multiple cancer typesand the expression levels correlate with severity of disease (see, e.g.,Macmillan, J. C. et al., Ann. Surg. Oncol., 2001, 8, 729-740). PLK1 isan oncogene and can transform NIH-3T3 cells (see, e.g., M. R. Smith etal., Biochem. Biophys. Res. Commun., 1997, 234, 397-405). Depletion orinhibition of PLK1 by siRNA, antisense, microinjection of antibodies, ortransfection of a dominant negative construct of PLK1 into cells,reduces proliferation and viability of tumor cells in vitro (see, e.g.,R. Guan et al., Cancer Res., 2005, 65, 2698-2704; X. Liu et al., Proc.Nat'l. Acad. Sci. U.S.A., 2003, 100, 5789-5794, Y. Fan et al., World J.Gastroenterol., 2005, 11, 4596-4599; H. A. Lane et al., J. Cell Biol.,1996, 135, 1701-1713). Tumor cells that have been depleted of PLK1 haveactivated spindle checkpoints and defects in spindle formation,chromosome alignment and separation and cytokinesis. Loss in viabilityhas been reported to be the result of an induction of apoptosis. Incontrast, normal cells have been reported to maintain viability ondepletion of PLK1. In vivo knock down of PLK1 by siRNA or the use ofdominant negative constructs leads to growth inhibition or regression oftumors in xenograft models.

PLK2 is mainly expressed during the G1 phase of the cell cycle and islocalized to the centrosome in interphase cells. PLK2 knockout micedevelop normally, are fertile and have normal survival rates, but arearound 20% smaller than wild type mice. Cells from knockout animalsprogress through the cell cycle more slowly than in normal mice (see,e.g., S. Ma et al., Mol. Cell. Biol., 2003, 23, 6936-6943). Depletion ofPLK2 by siRNA or transfection of kinase inactive mutants into cellsblocks centriole duplication. Down-regulation of PLK2 also sensitizestumor cells to taxol and promotes mitotic catastrophe, in part bysuppression of the p53 response (see, e.g., T. F. Burns et al., Mol.Cell. Biol., 2003, 23, 5556-5571).

PLK3 is expressed throughout the cell cycle and increases from G1 tomitosis. Expression is up-regulated in highly proliferating ovariantumors and breast cancer and is associated with a worse prognosis (see,e.g., W. Weichert et al., Br. J. Cancer, 2004, 90, 815-821; W. Weichertet al., Virchows Arch, 2005, 446, 442-450). In addition to regulation ofmitosis, PLK3 is believed to be involved in Golgi fragmentation duringthe cell cycle and in the DNA-damage response. Inhibition of PLK3 bydominant negative expression is reported to promote p53-independentapoptosis after DNA damage and suppresses colony formation by tumorcells (see, e.g., Z. Li et al., J. Biol. Chem., 2005, 280, 16843-16850).

PLK4 is structurally more diverse from the other PLK family members.Depletion of this kinase causes apoptosis in cancer cells (see, e.g., J.Li et al., Neoplasia, 2005, 7, 312-323). PLK4 knockout mice arrest atE7.5 with a high fraction of cells in mitosis and partly segregatedchromosomes (see, e.g., J. W. Hudson et al., Current Biology, 2001, 11,441-446).

Molecules of the protein kinase family have been implicated in tumorcell growth, proliferation and survival. Accordingly, there is a greatneed to develop compounds useful as inhibitors of protein kinases. Theevidence implicating the PLK kinases as essential for cell division isstrong. Blockade of the cell cycle is a clinically validated approach toinhibiting tumor cell proliferation and viability. It would therefore bedesirable to develop compounds that are useful as inhibitors of the PLKfamily of protein kinases (e.g., PLK1, PLK2, PLK3 and PLK4), that wouldinhibit proliferation and reduce viability of tumor cells, particularlyas there is a strong medical need to develop new treatments for cancer,including treatments that would be administered orally.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds of Formula Ishown and described herein, as well as their pharmaceutically acceptablesalts.

The compounds of this invention in general are potent inhibitors ofprotein kinases, such as PLKs (polo-like kinases), e.g., PLK1, PLK2,PLK3, or PLK4. Accordingly, these compounds and their pharmaceuticallyacceptable salts and compositions are useful for treating or preventingdiseases, disorders, or medical conditions implicated or mediated byprotein kinases such as PLKs (polo-like kinases), e.g., PLK1, PLK2,PLK3, or PLK4. Examples of such diseases or conditions include cancers,e.g., melanoma, myeloma, leukemia, lymphoma, neuroblastoma, coloncancer, breast cancer, gastric cancer, ovarian cancer, cervical cancer,lung cancer, central nervous system cancer, renal cancer, prostatecancer, bladder cancer, or pancreatic cancer.

The compounds provided by this invention are also useful for the studyof kinases in biological and pathological phenomena; the study ofintracellular signal transduction pathways mediated by such kinases; andthe comparative evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides compounds of the Formula I, or apharmaceutically acceptable salt thereof.

In Formula I,

Y is O or NR⁹;

R¹ is aryl or heteroaryl;

R² is H, alkyl, or cycloalkyl;

each of R³ and R⁴ is independently H, alkyl, cycloalkyl, aryl, orheteroaryl; or R³ and R⁴, together with the carbon atom to which theyare attached, form a cycloalkyl;

each of R⁵ and R⁶ is independently H, alkyl, cycloalkyl, aryl, orheteroaryl;

R⁷ is H, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;

R⁸ is alkyl;

R⁹ is H or alkyl; or R² and R⁹, together with the atoms to which theyare attached, optionally form a 5- to 8-membered monocyclic ringcontaining additional 0 to 2 hetero atoms each independently selectedfrom O, N, and S, wherein said monocyclic ring is optionally substitutedwith 0 to 4 groups each independently being alkyl, halo, alkoxy, orhydroxy; and

q is 0 or 1.

In some embodiments of compounds of this invention, Y is O.

In some embodiments, R² is alkyl (e.g., methyl or ethyl).

In some embodiments, R³ and R⁴ are independently H or alkyl (e.g.,methyl or ethyl).

In some embodiments, R³ and R⁴, together with the carbon atom to whichthey are attached, form a cycloalkyl (e.g., of C₃₋₅), thereby givingrise to a spiro ring system.

In some embodiments, R⁷ is alkyl or cycloalkyl (for examplecyclopentyl).

In some embodiments, each of R⁵ and R⁶ is independently H or alkyl(e.g., methyl, ethyl, or propyl).

In some embodiments, R⁸ is an optionally substituted alkyl (e.g.,methyl, ethyl, methoxymethyl, methoxyethyl, hydroxymethyl, orhydroxyethyl).

In some embodiments, when R⁸ is methyl, the carbon atom to which R⁸ isattached is generally in the S configuration; whereas when R⁸ is notmethyl (e.g., when it is hydroxymethyl, methoxymethyl, or ethyl), thesame carbon atom is generally in the R configuration.

In some embodiments, when R⁸ is methyl, the carbon atom to which R⁸ isattached is of the S configuration.

In some embodiments, R¹ is optionally substituted phenyl, optionallysubstituted napthyl, optionally substituted pyridyl, optionallysubstituted furanyl, or optionally substituted thiazolyl. The optionalsubstituents can range from 1 to 3 in number and can independently bealkyl (e.g., methyl or ethyl), halo (e.g., fluoro or chloro), amino(e.g., amino, dimethylamino, or (dimethylamino)ethyl)(methyl)amino),alkoxy (e.g., methoxy, trifluoromethoxy, or ethoxy), haloalkyl (e.g.,trifluoromethyl or chloroethyl), alkylsulfonyl (e.g.,tert-butylsulfonyl), nitro, phenyl, 1-piperazinyl, or4-alkylpiperazin-1-yl.

In some other embodiments, R¹ is phenyl optionally substituted with 1 to3 substituents each independently selected from the group consisting ofalkyl, halo, amino, alkoxy, haloalkyl, alkylsulfonyl, nitro, phenyl,1-piperazinyl, and 4-alkylpiperazin-1-yl.

In some further embodiments, R¹ is phenyl, 4-methylphenyl,4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl,4-(trifluoromethoxy)phenyl, 2-(trifluoromethyl)phenyl,4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl,3,5-bis(trifluoromethyl)phenyl, 4-bromophenyl, 4-chlorophenyl,4-fluorophenyl, 2-fluorophenyl, 3,5-difluorophenyl,4-(4-methylpiperazin-1-yl)phenyl, 4-(piperazin-1-yl)phenyl,4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl, 4-nitrophenyl,4-(methylsulfonyl)phenyl, biphenyl-4-yl, naphthalenyl, 3-pyridinyl,2-pyridinyl, 4-pyridinyl, 2-furanyl, 4-thiazolyl, or2-methylthiazol-4-yl.

Some compounds of this invention can be represented by Formula Ia:

wherein R¹ and R⁸ have been defined herein.

Some specific examples of the compounds of this invention include:

-   9-cyclopentyl-5,7,7-trimethyl-2-(1-phenylethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-5,7,7-trimethyl-2-(1-phenylpropylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-2-(2-methoxy-1-phenylethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-2-(2-hydroxy-1-phenylethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   2-(1-(4-bromophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one-   9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(piperazin-1-yl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-2-(1-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one-   9-cyclopentyl-5,7,7-trimethyl-2-(1-p-tolylethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   2-(1-(4-chlorophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-2-(1-(4-fluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-2-(1-(2-fluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-2-(1-(3,5-difluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-2-(1-(4-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-2-(1-(3-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-2-(1-(2-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-2-(1-(3,4-dimethoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(trifluoromethoxy)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-5,7,7-trimethyl-2-(1-(3-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   2-(1-(3,5-bis(trifluoromethyl)phenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-5,7,7-trimethyl-2-(1-(2-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-nitrophenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(methylsulfonyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   2-(1-(biphenyl-4-yl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-5,7,7-trimethyl-2-(1-(naphthalen-1-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-3-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-2-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one-   9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   9-cyclopentyl-2-(1-(furan-2-yl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;    or-   9-cyclopentyl-5,7,7-trimethyl-2-(1-(2-methylthiazol-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one.

In some embodiments of the compounds of this invention, q is 0.

In some other embodiments, each of R³ and R⁴ is independently H, oralkyl (e.g., methyl or ethyl)

In some further embodiments, R³ is ethyl and R⁴ is H.

In some embodiments, when R³ is ethyl and R⁴ is H, the carbon atom towhich R³ and R⁴ are attached is of the R configuration.

In some embodiments, R¹ is an optionally substituted aryl or optionallysubstituted heteroaryl. The optional substituents can range from 1 to 3in number and can each independently be alkyl, halo, amino, alkoxy,haloalkyl, alkylsulfonyl, nitro, phenyl, 1-piperazinyl, or4-methylpiperazin-1-yl.

In some further embodiments, R¹ is phenyl which is optionallysubstituted with 1 to 3 substituents each independently being alkyl(e.g., methyl or ethyl), halo (e.g., fluoro or chloro), amino (e.g.,amino, dimethylamino, or (dimethylamino)ethyl(methylamino)), alkoxy(e.g., methoxy, trifluoromethoxy, or ethoxy), haloalkyl (e.g.,trifluoromethyl or chloroethyl), alkylsulfonyl (e.g.,tert-butylsulfonyl), nitro, phenyl, 1-piperazinyl, or4-alkylpiperazin-1-yl.

In some embodiments, R⁸ is optionally substituted alkyl (e.g., methyl,ethyl, methoxymethyl, methoxyethyl, hydroxymethyl, or hydroxyethyl) oroptionally substituted cycloalkyl (e.g., cyclopropyl or cyclobutyl).

Some compounds of this invention can be represented by Formula Ib:

wherein R¹ and R⁸ are defined herein.

A further specific example of the compounds of this invention is:

-   8-cyclopentyl-7-ethyl-5-methyl-2-(1-phenylethylamino)-7,8-dihydropteridin-6(5H)-one.

In some other embodiments of the compounds of this invention, Y is NR⁹.

In some further embodiments, R² and R⁹, together with the atoms to whichthey are attached, form a 5- to 8-membered monocyclic ring containingadditional 0 to 2 hetero atoms each independently being O, N, or S, andthe monocyclic ring is optionally substituted with 0 to 4 substituentseach independently being halo or alkyl (e.g., methyl, chloromethyl, orethyl).

In some embodiments, Y is NR⁹ and q is 0.

In some embodiments, each of R³ and R⁴ is independently H or alkyl(e.g., methyl or ethyl).

In some further embodiments, R³ is ethyl and R⁴ is H.

In some embodiments, R⁷ is cycloalkyl (e.g., cyclopentyl) or aryl (e.g.,phenyl).

In some embodiments, R¹ is optionally substituted aryl (e.g.,p-bromophenyl) or optionally substituted heteroaryl (e.g.,4-methypiperazin-1-yl).

In some embodiments, R⁸ is alkyl (e.g., methyl, ethyl, methoxymethyl,methoxyethyl, hydroxymethyl, or hydroxyethyl).

Some compounds of this invention can be represented by Formula Ic:

Further examples of the compounds of this invention include:

-   5-cyclopentyl-4-ethyl-N-(1-phenylethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;-   N-(1-(4-bromophenyl)ethyl)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;-   5-cyclopentyl-4-ethyl-N-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;    or-   5-cyclopentyl-4-ethyl-N-(1-(4-(piperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine-   4-ethyl-5-phenyl-N-(1-phenylethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine

Additional examples of the compounds of this invention include thefollowing:

-   (S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-phenylethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-phenylpropylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (R)-9-cyclopentyl-2-(2-methoxy-1-phenylethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (R)-9-cyclopentyl-2-(2-hydroxy-1-phenylethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-2-(1-(4-bromophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-p-tolylethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-2-(1-(4-chlorophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-9-cyclopentyl-2-(1-(4-fluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-9-cyclopentyl-2-(1-(4-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-9-cyclopentyl-2-(1-(3-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-9-cyclopentyl-2-(1-(2-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(2-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-nitrophenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(methylsulfonyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (RS)-2-(1-(biphenyl-4-yl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(naphthalen-1-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-3-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (RS)-9-cyclopentyl-2-(1-(furan-2-yl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (RS)-9-cyclopentyl-2-(1-(3,4-dimethoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(trifluoromethoxy)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (R)—N—((S)-1-(4-bromophenyl)ethyl)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;-   (R)-5-cyclopentyl-4-ethyl-N—((S)-1-phenylethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;-   (R)-8-cyclopentyl-7-ethyl-5-methyl-2-((S)-1-phenylethylamino)-7,8-dihydropteridin-6(5H)-one;-   (S)-9-cyclopentyl-2-(1-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (R,    S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(2-methylthiazol-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(3-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (R,S)-9-cyclopentyl-2-(1-(2-fluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (R,S)-9-cyclopentyl-2-(1-(3,5-difluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (S)-2-(1-(3,5-bis(trifluoromethyl)phenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;-   (R)-4-ethyl-5-phenyl-N—((S)-1-phenylethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;-   (R)—N—((S)-1-(4-bromophenyl)ethyl)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;-   (R)-5-cyclopentyl-4-ethyl-N—((S)-1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;    and-   (R)-5-cyclopentyl-4-ethyl-N—((S)-1-(4-(piperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine.

Unless otherwise stated, structures depicted or described herein arealso meant to include all isomeric (e.g., enantiomeric, diastereomeric,geometric, or conformational) forms of the structures, e.g., the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Accordingly, singlestereochemical isomers as well as enantiomeric, diastereomeric,geometric, or conformational mixtures of the present compounds arewithin the scope of the invention. Likewise, unless otherwise stated,all tautomeric forms of the compounds of the invention are within thescope of the invention.

As used herein, the term “S configuration” or “R configuration” isconsistent with the commonly acceptable CIP system, as devised by R. S.Cahn, C. K. Ingold, and V. Prelog. For a detailed description of thesystem, see, e.g., IUPAC Rules for the Nomenclature of OrganicChemistry, Section E, Stereochemistry (Recommendations 1974), in Pure &Appl. Chem., Vol. 45, pp. 11-30, Pergamon Press, 1976 (Great Britain),the content of which is incorporated herein by reference in itsentirety.

Unless otherwise stated, the compounds of this invention include theirpharmaceutically acceptable salts, prodrugs, or derivatives.

As used herein, the term a “pharmaceutically acceptable salt” of acompound of this invention refers to a salt which, within the scope ofsound medical judgment, is suitable for use in contact with the tissuesof humans and lower animals without undue toxicity, irritation, allergicresponse and the like, and are commensurate with a reasonablebenefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in J. Pharm. Sci., 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. These salts can be prepared in situ during the finalisolation and purification of the compounds. Acid addition salts can beprepared, e.g., by first reacting the purified compound in itsfree-based form with a suitable organic or inorganic acid and thenisolating the salt thus formed.

Examples of pharmaceutically acceptable, nontoxic acid addition saltsare salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, glycolate, gluconate, hemisulfate,heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oleate, oxalate, palmitate, palmoate, pectinate, persulfate,3-phenylpropionate, phosphate, picrate, pivalate, propionate,salicylate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like. Saltsderived from appropriate bases include alkali metal, alkaline earthmetal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This invention also envisionsthe quaternization of any basic nitrogen-containing groups of thecompounds disclosed herein. Water or oil-soluble or dispersible productsmay be obtained by such quaternization.

Base addition salts can be prepared, e.g., by fist reacting the purifiedcompound in its acid form with a suitable organic or inorganic base andthen isolating the salt thus formed. Base addition salts include alkalior alkaline earth metal salts. Representative alkali or alkaline earthmetal salts include sodium, lithium, potassium, calcium, magnesium, andthe like. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counter ions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, or aryl sulfonate.Other acids and bases, while not in themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds of the invention and theirpharmaceutically acceptable acid or base addition salts.

A “pharmaceutically acceptable derivative” is an adduct or derivativewhich, upon administration to a patient in need, is capable ofproviding, directly or indirectly, a compound as otherwise describedherein, or a metabolite or residue thereof. Examples of pharmaceuticallyacceptable derivatives include, but are not limited to, esters and saltsof such esters.

A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable ester, salt of an ester or other derivativeof a compound of this invention which, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favoured derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

Pharmaceutically acceptable prodrugs of the compounds of this inventioninclude, but are not limited to, esters, amino acid esters, phosphateesters, metal salts, and sulfonate esters.

The compounds of this invention in general exhibit unexpected highactivities in inhibiting protein kinases, e.g., PLKs (such as PLK1), andthus can be used for treatment of diseases, disorders, or medicalconditions mediated by these protein kinases.

Accordingly, the present invention also provides pharmaceuticalcompositions each containing one or more of the compounds described orspecifically named above and a pharmaceutically acceptable carrier,adjuvant, or vehicle.

In certain embodiments, these compositions optionally further compriseone or more additional therapeutic agents. For instance,chemotherapeutic agents or other anti-proliferative agents may becombined with the compounds of this invention to treat proliferativediseases and cancer.

Examples of known chemotherapeutic agents include, but are not limitedto, Gleevec™, adriamycin, dexamethasone, vincristine, cyclophosphamide,fluorouracil, topotecan, taxol, interferons, and platinum derivatives.

Other examples of agents with which the compounds of this invention mayalso be combined include, but are not limited to, agents for treatingAlzheimer's Disease such as Aricept® and Excelon®; treatments forParkinson's Disease such as L-DOPA/carbidopa, entacapone, ropinrole,pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine;agents for treating Multiple Sclerosis (MS) such as beta interferon(e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments forasthma such as albuterol and Singulair®; agents for treatingschizophrenia such as zyprexa, risperdal, seroquel, and haloperidol;anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA,azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

As described herein, a “pharmaceutically acceptable carrier, adjuvant,or vehicle,” as used herein, refers to any and all solvents, diluents,or other liquid vehicle, dispersion or suspension aids, surface activeagents, isotonic agents, thickening or emulsifying agents,preservatives, solid binders, lubricants and the like, as suited to theparticular dosage form desired. Remington's Pharmaceutical Sciences,Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980)discloses various carriers used in formulating pharmaceuticallyacceptable compositions and known techniques for the preparationthereof. Except insofar as any conventional carrier medium isincompatible with the compounds of the invention, such as by producingany undesirable biological effect or otherwise interacting in adeleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The compounds of this invention or pharmaceutical salts thereof may beformulated into pharmaceutically acceptable compositions foradministration to animals or humans.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect. In a preferred embodiment, compounds of thisinvention are administered orally.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it may be desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes, but is not limited to, subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Preferably, the compositions areadministered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include, but arenot limited to, lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added. For oral administration ina capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening, flavoring or coloring agents may also beadded.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient that is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include, but are not limited to, cocoa butter, beeswaxand polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of protein kinase inhibitor that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated, the particular mode of administration.Preferably, the compositions should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of the inhibitor can beadministered to a patient receiving these compositions.

As mentioned above, the compounds of this invention in general haveunexpectedly high inhibitory effect on protein kinases such as PLKs(e.g., PLK1, PLK2, PLK3, or PLK4), which are often involved inproliferative disorders, neurodegenerative disorders, autoimmunedisorders, inflammatory disorders, and immunologically mediateddisorders.

Additionally, the invention provides a method for inhibiting a proteinkinase (such as PLK (e.g., PLK1)) by contacting the protein kinase withone or more compounds of this invention or a pharmaceutically acceptablecomposition of this invention. Examples of protein kinase that can be soinhibited include PLKs (e.g., PLK1 or PLK2).

In another aspect, the present invention provides a method forinhibiting a protein kinase in a patient, which includes administeringto the patient in need of such treatment a pharmaceutically effectiveamount of one or more compounds of this invention (described above), ora pharmaceutical composition of this invention. The protein kinase inthe patient can be a PLK (e.g., PLK1 or PLK2).

The invention also provides methods for treating or preventing a proteinkinase-mediated condition (in some embodiments, a PLK-mediatedcondition) comprising the step of administering to a patient one of theabove-described pharmaceutical compositions. The term “patient”, as usedherein, means an animal, preferably a human.

In some embodiments, the methods are used to treat or prevent a disease,disorder, or medical condition which is selected from a proliferativedisorder, a neurodegenerative disorder, an autoimmune disorder, aninflammatory disorder, or an immunologically-mediated disorder.

Examples of proliferative disorders include cancers, which can be, e.g.,cancers of the breast, colon, prostate, skin, pancreas, brain,genitourinary tract, lymphatic system, stomach, larynx and lung,including lung adenocarcinoma and small cell lung cancer; stroke,diabetes, myeloma, hepatomegaly, cardiomegaly, Alzheimer's disease,cystic fibrosis, and viral disease, or any specific disease describedabove.

In some embodiments, the methods of this invention can further includeadministering to the patient a chemotherapeutic agent, ananti-proliferative agent, an anti-inflammatory agent, animmunomodulatory agent, an immunosuppressive agent, a neurotrophicfactor, an agent for treating cardiovascular disease, an agent fortreating destructive bone disorder, an agent for treating liver disease,an anti-viral agent, an agent for treating blood disorder, an agent fortreating diabetes, or an agent for treating immunodeficiency disorder,in addition to one or more compounds or pharmaceutical composition ofthis invention.

In yet another aspect, the present invention provides a method fortreating cancer (such as melanoma, myeloma, leukemia, lymphoma,neuroblastoma, colon cancer, breast cancer, gastric cancer, ovariancancer, cervical cancer, lung cancer, central nervous system cancer,renal cancer, prostate cancer, bladder cancer, or pancreatic cancer) ina patient, which includes administering to the patient in need thereof apharmaceutically effective amount of one or more compounds of thisinvention or a pharmaceutical composition of this invention.

Also provided by the method of invention is a method for disruptingmitosis of cancer cells by inhibiting PLKs, which includes using one ormore compounds of this invention described by any of the aboveembodiments.

One aspect of this invention provides compounds that are useful for thetreatment of diseases, disorders, and conditions characterized byexcessive or abonormal cell proliferation, by administering to a subjectin need thereof an effective amount of a compound of this invention, ora pharmaceutically acceptable composition comprising a compound of thisinvention. Such diseases include, but are not limited to, proliferativeor hyperproliferative diseases (e.g., cancer), and neurodegenerativediseases (e.g., Alzheimer's disease).

As used herein, an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective inorder to treat a target disease. The compound and composition, accordingto the method of the present invention, may be administered using anyamount and any route of administration effective for treating orlessening the severity of the target disease.

The exact amount of compound required for treatment will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like. The compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of the compounds and compositions of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient,” as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of inhibitor will also depend upon the particular compound in thecomposition.

In some embodiments, the compounds of this invention are useful fortreating cancer (such as colorectal, thyroid, breast, and lung cancer)and myeloproliferative disorders (such as polycythemia vera,thrombocythemia, myeloid metaplasia with myelofibrosis, chronicmyelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilicsyndrome, juvenile myelomonocytic leukemia, and systemic mast celldisease).

As used herein, the term “cancer” includes, but is not limited to, thefollowing cancers: breast; ovary; cervix; prostate; testis,genitourinary tract; esophagus; larynx, glioblastoma; neuroblastoma;stomach; skin, keratoacanthoma; lung, epidermoid carcinoma, large cellcarcinoma, small cell carcinoma, lung adenocarcinoma; bone; colon;colorectal; adenoma; pancreas, adenocarcinoma; thyroid, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma; seminoma;melanoma; sarcoma; bladder carcinoma; liver carcinoma and biliarypassages; kidney carcinoma; myeloid disorders; lymphoid disorders,Hodgkin's, hairy cells; buccal cavity and pharynx (oral), lip, tongue,mouth, pharynx; small intestine; colon-rectum, large intestine, rectum;brain and central nervous system; chronic myeloid leukemia (CML);leukaemia; myeloma; lymphoma; gastric; renal; head and neck;oropharangeal; non-small cell lung cancer (NSCLC); endometrial;hepatocarcinoma; Non-Hodgkins lymphoma; and pulmonary.

For the avoidance of doubt, the term “cancer” also includes, but is notlimited to, the following cancers: epidermoid Oral: buccal cavity, lip,tongue, mouth, pharynx; Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell or epidermoid,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, larynx,adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel or smallintestines (adenocarcinoma, lymphoma, carcinoid tumors, Karposi'ssarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), largebowel or large intestines (adenocarcinoma, tubular adenoma, villousadenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal; rectum,Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast;Hematologic: blood (myeloid leukemia [acute and chronic], acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma [malignant lymphoma] hairy cell;lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis,Thyroid gland: papillary thyroid carcinoma, follicular thyroidcarcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer,multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma;and Adrenal glands: neuroblastoma. As used herein, the term “cancerouscell” includes a cell afflicted by any one of the above-identifiedconditions.

In some embodiments, the compounds of this invention are useful fortreating hematopoietic disorders. Examples of such hematopoieticdisorders include, but are not limited to, acute-myelogenous leukemia(AML), chronic-myelogenous leukemia (CML), acute-promyelocytic leukemia(APL), and acute lymphocytic leukemia (ALL).

In some embodiments, the disease that can be treated by the methods ofthis invention is a protein kinase-mediated disease, disorder, ormedical condition. Examples of the protein kinase that mediates such adisease, disorder, or medical condition include, but are not limited to,PLKs (e.g., PLK1, PLK2, PLK3, and PLK4).

The term “protein kinase-mediated condition,” as used herein, means anydisease, disorder, or other deleterious condition in which a proteinkinase plays a role. Such conditions include, but are not limited to,autoimmune diseases, inflammatory diseases, proliferative andhyperproliferative diseases, immunologically-mediated diseases, bonediseases, metabolic diseases, neurological and neurodegenerativediseases, cardiovascular diseases, hormone related diseases, allergies,asthma, and Alzheimer's disease.

The term “PLK-mediated condition”, as used herein, means any disease orother deleterious condition in which PLK plays a role. Examples of sucha disease or condition include, but are not limited to, proliferative orhyperproliferative diseases, or neurodegenerative diseases.

The compounds of this invention include those described herein, and arefurther illustrated by the classes, subclasses, and species disclosedherein. As used herein, the following definitions shall apply unlessotherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described inOrganic Chemistry, Thomas Sorrell, University Science Books, Sausalito(1999), and March's Advanced Organic Chemistry, 5^(th) Ed. (Eds.: M. B.Smith and J. March), John Wiley & Sons, New York (2001), the entirecontents of which are incorporated herein by reference.

As described herein, a specified number range includes any integertherein, as well as the upper and lower limits thereof. For example, agroup having 1-4 (i.e., from 1 to 4) atoms could have 1, 2, 3, or 4atoms.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds.

The term “stable”, as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, recovery, purification, and use for one or moreof the purposes disclosed herein. In some embodiments, a stable compoundor chemically feasible compound is one that is not substantially alteredwhen kept at a temperature of 40° C. or lower, in the absence ofmoisture or other chemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group,” as used herein, means astraight-chain (i.e., unbranched), branched, or cyclic substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation that has a single point ofattachment to the rest of the molecule. Unless otherwise specified,aliphatic groups contain 1-20 (e.g., 1-10, 1-8, 1-6, or 1-4) aliphaticcarbon atoms. It should be understood that if the aliphatic is alkenylor alkynyl, then it has at least 2 carbon atoms.

Suitable aliphatic groups encompass linear or branched, substituted orunsubstituted alkyl, alkenyl, or alkynyl groups. Specific examplesinclude, but are not limited to, methyl, ethyl, isopropyl, n-propyl,sec-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl.

As used herein, an “alkyl” group refers to a saturated aliphatichydrocarbon group containing 1 to 12 (e.g., 1 to 10, 1 to 8, 1 to 6, or1 to 4) carbon atoms. An alkyl group can be straight or branched.Examples of alkyl groups include, but are not limited to, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,n-heptyl, or 2-ethylhexyl. An alkyl group can be substituted (i.e.,optionally substituted) with one or more substituents such as halo,phospho, cycloaliphatic (e.g., cycloalkyl or cycloalkenyl),heterocycloaliphatic (e.g., heterocycloalkyl or heterocycloalkenyl),aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl (e.g.,(aliphatic)carbonyl, (cycloaliphatic)carbonyl, or(heterocycloaliphatic)carbonyl), nitro, cyano, amido (e.g.,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,arylaminocarbonyl, or heteroarylaminocarbonyl), amino (e.g.,aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino),sulfonyl (e.g., aliphatic-SO2-), sulfinyl, sulfanyl, sulfoxy, urea,thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl,cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy,aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, orhydroxy. Without limitation, some examples of substituted alkyls includecarboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, andalkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl,acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as(alkyl-SO2-amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl,or haloalkyl.

As used herein, an “alkenyl” group refers to an aliphatic carbon groupthat contains 2 to 12 (e.g., 2 to 8, 2 to 6, or 2 to 4) carbon atoms andat least one double bond. Like an alkyl group, an alkenyl group can bestraight or branched. Examples of an alkenyl group include, but are notlimited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl groupcan be optionally substituted with one or more substituents such ashalo, phospho, cycloaliphatic (e.g., cycloalkyl or cycloalkenyl),heterocycloaliphatic (e.g., heterocycloalkyl or heterocycloalkenyl),aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl (e.g.,(aliphatic)carbonyl, (cycloaliphatic)carbonyl, or(heterocycloaliphatic)carbonyl), nitro, cyano, amido (e.g.,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,arylaminocarbonyl, or heteroarylaminocarbonyl), amino (e.g.,aliphaticamino, cycloaliphaticamino, heterocycloaliphaticamino, oraliphaticsulfonylamino), sulfonyl (e.g., alkyl-SO2-,cycloaliphatic-SO2-, or aryl-SO2-), sulfinyl, sulfanyl, sulfoxy, urea,thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl,cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy,aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, orhydroxy. Without limitation, some examples of substituted alkenylsinclude cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl,aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (such as(alkyl-SO2-amino)alkenyl), aminoalkenyl, amidoalkenyl,(cycloaliphatic)alkenyl, or haloalkenyl.

As used herein, an “alkynyl” group refers to an aliphatic carbon groupthat contains 2 to 12 (e.g., 2 to 8, 2 to 6, or 2 to 4) carbon atoms andhas at least one triple bond. An alkynyl group can be straight orbranched. Examples of an alkynyl group include, but are not limited to,propargyl and butynyl. An alkynyl group can be optionally substitutedwith one or more substituents such as aroyl, heteroaroyl, alkoxy,cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl (e.g.,aliphaticsulfanyl or cycloaliphaticsulfanyl), sulfinyl (e.g.,aliphaticsulfinyl or cycloaliphaticsulfinyl), sulfonyl (e.g.,aliphatic-SO2-, aliphaticamino-SO2-, or cycloaliphatic-SO2-), amido(e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino,heteroarylcarbonylamino or heteroarylaminocarbonyl), urea, thiourea,sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic,heterocycloaliphatic, aryl, heteroaryl, acyl (e.g.,(cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl), amino(e.g., aliphaticamino), sulfoxy, oxo, carboxy, carbamoyl,(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.

The term “protecting group,” as used herein, represents those groupsintended to protect a functional group, such as, for example, analcohol, amine, carboxyl, carbonyl, etc., against undesirable reactionsduring synthetic procedures. Commonly used protecting groups aredisclosed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Edition (John Wiley & Sons, New York, 1999), which is incorporatedherein by reference. Examples of nitrogen protecting groups includeacyl, aroyl, or carbamyl groups such as formyl, acetyl, propionyl,pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl,trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl,benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and chiralauxiliaries such as protected or unprotected D, L or D, L-amino acidssuch as alanine, leucine, phenylalanine and the like; sulfonyl groupssuch as benzenesulfonyl, p-toluenesulfonyl and the like; carbamategroups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike, arylalkyl groups such as benzyl, triphenylmethyl, benzyloxymethyland the like and silyl groups such as trimethylsilyl and the like.Preferred N-protecting groups are tert-butyloxycarbonyl (Boc).

Examples of useful protecting groups for acids are substituted alkylesters such as 9-fluorenylmethyl, methoxymethyl, methylthiomethyl,tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl,2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, pivaloyloxymethyl,phenylacetoxymethyl, triisopropropylsysilylmethyl, cyanomethyl, acetol,phenacyl, substituted phenacyl esters, 2,2,2-trichloroethyl,2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl,t-butyl, 3-methyl-3-pentyl, dicyclopropylmethyl, cyclopentyl,cyclohexyl, allyl, methallyl, cynnamyl, phenyl, silyl esters, benzyl andsubstituted benzyl esters, 2,6-dialkylphenyl esters such aspentafluorophenyl, 2,6-dialkylpyhenyl. Preferred protecting groups foracids are methyl or ethyl esters.

Methods of adding (a process generally referred to as “protection”) andremoving (process generally referred to as “deprotection”) such amineand acid protecting groups are well-known in the art and available, forexample in P. J. Kocienski, Protecting Groups, Thieme, 1994, which ishereby incorporated by reference in its entirety and in Greene and Wuts,Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons,New York, 1999).

As used herein, the term, “leaving group” refers to an atom or group(charged or uncharged) that becomes detached from an atom in what isconsidered to be the residual or main part of the substrate in aspecified reaction. For example, in the heterolytic solvolysis of benzylbromide in acetic acid:

the leaving group is Br—; The term has meaning only in relation to aspecified reaction. The leaving group is not, in general, the same asthe substituent group present in the substrate (e.g. bromo andtrimethylammonio in the substrates of the first two examples above.) Aslightly different usage of the term prevails in the (non-mechanistic)naming of transformations, where the actual substituent group present inthe substrate (and also in the product) is referred to as the leavinggroup (IUPAC. Compendium of Chemical Terminology, 2nd ed. (the “GoldBook”). Compiled by A. D. McNaught and A. Wilkinson. BlackwellScientific Publications, Oxford (1997). XML on-line corrected version:http://goldbook.iupac.org (2006-) created by M. Nic, J. Jirat, B.Kosata; updates compiled by A. Jenkins).

The term “cycloaliphatic” refers to a monocyclic C₃₋₈ hydrocarbon orbicyclic C₇₋₁₂ hydrocarbon that is completely saturated or contains oneor more units of unsaturation, but is not aromatic, and has a singlepoint of attachment to the rest of the molecule wherein any individualring in said bicyclic ring system has 3-7 members. Suitablecycloaliphatic groups include, but are not limited to, cycloalkyl andcycloalkenyl groups. Specific examples include, but are not limited to,cyclohexyl, cyclopentanyl, cyclopropenyl, and cyclobutyl. The term“heteroaliphatic”, as used herein, means aliphatic groups wherein one ormore chain carbon atoms are independently replaced by an oxygen, sulfur,nitrogen, phosphorus, or silicon. Heteroaliphatic groups may besubstituted or unsubstituted, branched or unbranched, cyclic or acyclic,and include “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or“heterocyclic” groups. The term “heterocycle”, “heterocyclyl”, and“heterocyclic” as used herein are interchangeable and mean non-aromatic,monocyclic, bicyclic, or tricyclic ring systems in which one or morering members are an independently selected heteroatom. In someembodiments, the “heterocycle”, “heterocyclyl”, or “heterocyclic” grouphas three to fourteen ring members in which one or more ring members isa hetero atom independently selected from oxygen, sulfur, nitrogen, orphosphorus, and each ring in the system contains 3 to 7 ring members.

Examples of suitable heterocycles include, but are not limited to,3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl,2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl,4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl,4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,5-imidazolidinyl, indolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and1,3-dihydro-imidazol-2-one.

Cyclic groups, (e.g., cycloaliphatic and heterocycles), can be linearlyfused, bridged, or spirocyclic.

The term “heteroatom” or “hetero atom” means oxygen, sulfur, nitrogen,or phosphorus atom, including any oxidized form of nitrogen, sulfur, orphosphorus; the quarternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, e.g., N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR′ (as inN-substituted pyrrolidinyl).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “nonaromatic”, as used herein, describes rings that are eithersaturated or partially unsaturated.

The term “aromatic”, as used herein, describes rings that are fullyunsaturated.

The term “alkoxy” or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy”mean alkyl, alkenyl or alkoxy, as the case may be, substituted with oneor more halogen atoms. The terms “halogen”, “halo”, and “hal” mean F,Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring.”

An example of aryl is phenyl. Unless otherwise stated, aryl isoptionally substituted and each of the optional substituents (e.g., 2 or3 optional substituents) independently can be alkyl, halo, amino,alkoxy, haloalkyl, alkylsulfonyl, nitro, phenyl, piperazinyl (e.g.,piperazin-1-yl or piperazin-4-yl), and 4-alkylpiperazin-1-yl.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more hetero atoms, and whereineach ring contains 3 to 7 ring members. The term “heteroaryl” may beused interchangeably with the term “heteroaryl ring” or“heteroaromatic”. Examples of suitable heteroaryl include, but are notlimited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl),2-thiazolyl, 4-thiazolyl, 2-methylthiazol-4-yl, 5-thiazolyl, tetrazolyl(e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl),2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e.g.,2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl,1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl(e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl(e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

The terms “protecting group” and “protective group,” as used herein, areinterchangeable and refer to an agent used to temporarily block one ormore desired reactive sites in a multifunctional compound. In certainembodiments, a protecting group has one or more, or preferably all, ofthe following characteristics: a) it is added selectively to afunctional group in good yield to give a protected substrate that is b)stable to reactions occurring at one or more of the other reactivesites; and c) is selectively removable in good yield by reagents that donot attack the regenerated, deprotected functional group. Exemplaryprotecting groups are detailed by T. W. Greene et al. in ProtectiveGroups in Organic Synthesis, Third Edition, John Wiley & Sons, New York(1999) (and other editions of the book), the entire contents of whichare incorporated herein by reference.

The term “nitrogen protecting group,” as used herein, refers to an agentused to temporarily block one or more desired nitrogen reactive sites ina multifunctional compound. Suitable nitrogen protecting groups alsopossess the characteristics described above, and some examples nitrogenprotecting groups are provided by T. W. Greene et al. in Chapter 7 ofProtective Groups in Organic Synthesis, supra.

In some embodiments, an alkyl or aliphatic chain can be optionallyinterrupted with another atom or group. This means that a methylene unitof the alkyl or aliphatic chain is optionally replaced with the otheratom or group. Examples of such other atom or group include, but are notlimited to, —NR—, —O—, —S—, —CO₂—, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NR—,—C(═N—CN)—, —NRCO—, —NRC(O)O—, —SO₂NR—, —NRSO₂—, —NRC(O)NR—, —OC(O)NR—,—NRSO₂NR—,

—SO—, or —SO₂—, wherein R is defined herein. Unless otherwise specified,the optional replacements form a chemically stable compound. Optionalinterruptions can occur within the chain or at either end of the chain;i.e., both at the point of attachment or also at a terminal end. Twooptional replacements can also be adjacent to each other within a chainas long as it results in a chemically stable compound. The optionalinterruptions or replacements can also completely replace all of thecarbon atoms in a chain. For example, a C₃ aliphatic can be optionallyinterrupted or replaced by —NR—, —C(O)—, and —NR— to form —NRC(O)NR—(urea). Unless otherwise specified, if the replacement or interruptionoccurs at a terminal end, the replacement atom is bound to an H on theterminal end. For example, if —CH₂CH₂CH₃ is optionally interrupted with—O—, the resulting compound could be —OCH₂CH₃, —CH₂OCH₃, or —CH₂CH₂OH.

Unless otherwise stated, a substituent can freely rotate around anyrotatable bonds. For example, a substituent drawn

as also represents

Additionally, unless otherwise stated, structures depicted or describedherein are also meant to include compounds that differ only in thepresence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C— or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

The following abbreviations are used here:

-   -   PG protecting group    -   LG leaving group    -   DCM dichloromethane    -   Ac acetyl    -   DMF dimethylformamide    -   EtOAc ethyl acetate    -   DMSO dimethyl sulfoxide    -   MeCN acetonitrile    -   TCA trichloroacetic acid    -   ATP adenosine triphosphate    -   EtOH ethanol    -   Ph phenyl    -   Me methyl    -   Et ethyl    -   Bu butyl    -   DEAD diethylazodicarboxylate    -   HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid    -   BSA bovine serum albumin    -   DTT dithiothreitol    -   MOPS 4-morpholinepropanesulfonic acid    -   NMR nuclear magnetic resonance    -   HPLC high performance liquid chromatography    -   LCMS liquid chromatography-mass spectrometry    -   TLC thin layer chromatography

General Synthetic Methods

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art such as, e.g., those depicted in thegeneral schemes below. Unless otherwise indicated, all variables in thefollowing schemes are as defined herein. These compounds may be analyzedby known methods such as, e.g., MS (mass spectrometry), LCMS (liquidchromatography mass spectrometry), and NMR (nuclear magnetic resonance).

In one method, compounds of the invention wherein Y is O may be preparedas illustrated in Scheme 1.

Referring to Scheme 1, the nitro pyrimidine 1, wherein LG₁ and LG₂ are,e.g., chlorine, reacts with α- or β-aminoesters 2 (when n is 0 or 1) toprovide an adduct 3. Reduction of the nitro group under knownconditions, followed by cyclization, provides a bicyclic compound 4. Theamide N—H may be functionalized by reaction with, e.g., an alkyl halidein the presence of a strong base such as, e.g., sodium hydride toprovide compound 5. Reaction of compound 5 with R¹C(R⁸)NH₂, optionallyin the presence of a palladium catalyst, provides compounds of FormulaI.

An alternative method for preparing compounds of Formula I is shown inScheme 2.

Referring to Scheme 2, the intermediate 3, wherein LG₂ is, e.g.,chlorine, reacts with R¹C(R⁸)NH₂, optionally in the presence of apalladium catalyst, to provide 6. Reduction of the nitro group aspreviously described, followed by cyclization provides a bicycliccompound 7. The amide N—H is functionalized as previously described toprovide compounds of formula I.

Preparation of compounds of this invention in which Y is NR⁹, and R⁹ andR² together with the atoms to which they are attached form a triazolering is shown in Scheme 3.

Referring to Scheme 3, activation of the lactam functional group incompound 4 provides an intermediate 8 wherein LG₃ is, e.g., chlorine,followed by displacement with hydrazine provides a second intermediate9. Reaction of intermediate 9 with an orthoformate ester (e.g., methylorthoformate) provides a triazole intermediate 10. Reaction ofintermediate 10 with R¹C(R⁸)NH₂ as previously described provides acompound of Formula I-B.

The compounds of this invention in general are potent inhibitors ofprotein kinases such as PLKs, e.g., PLK1, pLK2, PLK3, or PLK4. In someinstances, the compounds of this invention demonstrate PLK1 inhibitionat concentrations of less than 10 nM. In other instances, the compoundsof this invention demonstrate PLK1 inhibition at concentrations of lessthan 1 nM. Further, the compounds of the invention demonstrateadvantageous pharmaco-kinetic properties.

As potent inhibitors of protein kinases (e.g., PLKs such as PLK1 orPLK2), the compounds of this invention and compositions containing thesame are useful for treating or lessening the severity or indications ofa disease, disorder, or condition wherein a protein kinase (e.g., PLKssuch as PLK1 or PLK2) is implicated. Accordingly, the invention includesmethods for treatment, lessening the severity or indications, orprevention of such diseases, disorders, or conditions with compounds ofcompositions of this invention.

Examples of such diseases, disorders, or conditions include, but are notlimited to, autoimmune diseases, inflammatory diseases, proliferativediseases, hyperproliferative diseases, immunologically-mediateddiseases, bone diseases, metabolic diseases, neurological diseases,neurodegenerative diseases, cardiovascular diseases, hormone relateddiseases, allergies, asthma, and Alzheimer's disease.

Depending upon the particular protein kinase-mediated disease, disorder,or condition to be treated or prevented, one or more additional drugs,which are normally administered to treat or prevent that disease,disorder, or condition may be administered together with the inhibitorsof this invention. For example, chemotherapeutic agents or otheranti-proliferative agents may be combined with the compounds of thisinvention to treat proliferative diseases.

Those additional agents may be administered separately, as part of amultiple dosage regimen, from the compounds of this invention orpharmaceutical compositions containing them. Alternatively, one or moreof those additional agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition.

As inhibitors of protein kinases, the compounds and compositions of thisinvention are also useful in biological samples. One aspect of theinvention relates to inhibiting protein kinase activity in a biologicalsample, which includes contacting the biological sample with a compoundof Formula I or a composition containing the compound. The term“biological sample”, as used herein, means an in vitro or an ex vivosample. Examples of biological samples include, but are not limited to,cell cultures, biopsied material obtained from a mammal, blood, saliva,urine, feces, semen, tears, or other body fluids, or extracts thereof.

Inhibition of protein kinase activity in a biological sample is usefulfor a variety of purposes that are known to one of skill in the art.Examples of such purposes include, but are not limited to, bloodtransfusion, organ-transplantation, and biological specimen storage.

Accordingly, another aspect of this invention relates to the study ofprotein kinases in biological and pathological phenomena; the study ofintracellular signal transduction pathways mediated by such proteinkinases; and the comparative evaluation of new protein kinaseinhibitors. Examples of such uses include, but are not limited to,biological assays such as enzyme assays and cell-based assays.

The activity of the compounds as protein kinase inhibitors may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the kinase activity or ATPaseactivity of the activated kinase. Alternate in vitro assays quantitatethe ability of the inhibitor to bind to the protein kinase and may bemeasured either by radio-labeling the inhibitor prior to binding,isolating the inhibitor/kinase complex and determining the amount ofradiolabel bound, or by running a competition experiment where newinhibitors are incubated with the kinase bound to known radio-ligands.Detailed conditions for assaying a compound utilized in this inventionas an inhibitor of PLK1, PLK2, PLK3, and PLK4 are set forth in theExamples below.

Set forth below are some specific examples of the compounds of thisinvention, and their preparation and assays for activities. It should beunderstood that these examples and specific conditions illustrated anddescribed below are demonstrative only, and should not be construed tolimit the scope of this invention.

Example 1(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-phenylethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

2-Chloro-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one(100 mg, 0.3238 mmol, prepared as described in WO 2007/095188) wasdissolved in n-butyl alcohol (1 mL). To the butyl alcohol solution thusobtained were then added (1S)-1-phenylethanamine (750 μL, 5.830 mmol)and DIPEA (167.4 mg, 225.6 μL, 1.295 mmol). The resulting solution washeated at 140° C. in microwave for 90 minutes. Additional(1S)-1-phenylethanamine (500 μL, 3.887 mmol) was added and the reactionmixture heated for 90 minutes in microwave at 140° C. The solvent wasremoved in vacuo and the residue dissolved in dichloromethane and washedsequentially with 0.5M HCl (three times, 5 mL each), saturated aqueoussodium hydrogen carbonate solution (three times, 5 mL each), and brine(once, 5 mL). The washed solution was dried over MgSO₄, filtered, andconcentrated in vacuo to give yellow oil. The oil was purified by massdirected HPLC and the product fractions passed through a bicarbonatecartridge and lypholized to afford the title compound as a white solid(33.5 mg, 26% yield).

¹H NMR (DMSO-d₆, 400 MHz): δ 1.01 (d, 6H), 1.38 (d, 3H), 1.38-1.48 (m,2H), 1.52-1.68 (m, 4H), 1.77-1.97 (m, 1H), 3.08 (s, 3H), 3.15-3.25 (m,2H), 4.84 (br s, 2H), 7.14-7.18 (m, 2H), 7.24-7.28 (m, 2H), 7.31-7.34(m, 2H), 7.37 (s, 1H).

MS (ES+) 394, (ES−) 392.

Shown in the following table are other compounds that were prepared by amethod similar to that used for preparing Example 1.

Example No. Name of Compound Physical Data 2 (S)-9-cyclopentyl-5,7,7- ¹HNMR (DMSO-d₆, 400 MHz): trimethyl-2-(1- δ 0.86 (s, 3H), 1.01 (s,phenylpropylamino)-8,9- 6H), 1.23-1.70 (m, 8H), dihydro-5H-pyrimido[4,5-1.78-1.83 (m, 2H), 3.08 (s, 3H), b][1,4]diazepin-6(7H)-one 3.14-3.26 (m,2H), 4.60 (br s, 1H), 5.00 (br s, 1H), 7.16-7.30 (m, 6H), 7.72 (br s,1H). MS (ES+) 408, (ES−) 406. 3 (R)-9-cyclopentyl-2-(2- ¹H NMR (DMSO-d₆,400 MHz): methoxy-1- δ 1.02 (s, 6H), phenylethylamino)-5,7,7- 1.41-1.75(m, 7H), 1.87-1.92 (m, trimethyl-8,9-dihydro-5H- 1H), 3.09 (s, 3H),pyrimido[4,5- 3.17-3.22 (m, 2H), 3.23 (s, 3H), b][1,4]diazepin-6(7H)-one3.41-3.62 (m, 3H), 5.05-5.10 (br m, 1H), 7.02 (br s, 1H), 7.17-7.42 (m,5H), 7.75 (s, 1H). MS (ES+) 424, (ES−) 422. 4 (R)-9-cyclopentyl-2-(2- ¹HNMR (DMSO-d₆, 400 MHz): hydroxy-1- δ 1.01 (s, 6H),phenylethylamino)-5,7,7- 1.36-1.68 (m, 7H), 1.83-1.86 (m,trimethyl-8,9-dihydro-5H- 1H), 3.09 (s, 3H), pyrimido[4,5- 3.18-3.26 (m,2H), 3.58 (s, 2H), 4.86 (br b][1,4]diazepin-6(7H)-one m, 2H), 6.84 (m,1H), 7.18-7.35 (m, 6H), 7.75 (s, 1H). MS (ES+) 410, (ES−) 408. 5(S)-2-(1-(4- ¹H NMR (DMSO-d₆, 400 MHz): bromophenyl)ethylamino)- δ 1.01(d, 6H), 1.37 (d, 9-cyclopentyl-5,7,7- 3H), 1.36-1.46 (m, 4H),trimethyl-8,9-dihydro-5H- 1.47-1.65 (m, 3H), 1.75-1.82 (m, pyrimido[4,5-1H), 3.09 (s, 3H), b][1,4]diazepin-6(7H)-one 3.17-3.26 (m, 2H), 4.81 (brs, 2H), 7.18 (br s, 1H), 7.28 (d, 2H), 7.46 (d, 2H), 7.74 (s, 1H). MS(ES+) 472, (ES−) 470. 7 (S)-9-cyclopentyl-5,7,7- ¹H NMR (DMSO-d₆, 400MHz): trimethyl-2-(1-p- δ 1.02 (d, 6H), 1.36 (d, tolylethylamino)-8,9-3H), 1.24-1.48 (m, 4H), dihydro-5H-pyrimido[4,5- 1.62-1.69 (m, 3H),1.80-1.85 (m, b][1,4]diazepin-6(7H)-one 1H), 2.24 (s, 3H), 3.08 (s, 3H),3.19-3.25 (m, 2H), 4.81-5.09 (br m, 2H), 7.07 (m, 3H), 7.21 (d, 2H),7.73 (s, 1H). MS (ES+) 408, (ES−) 406. 8 (S)-2-(1-(4- 1H NMR (DMSO-d6,400 MHz) chlorophenyl)ethylamino)- δ 1.01 (d, 6H), 1.37 (d,9-cyclopentyl-5,7,7- 4H), 1.40-1.50 (m, 2H), trimethyl-8,9-dihydro-5H-1.50-1.65 (m, 4H), 1.75-1.85 (m, pyrimido[4,5- 1H), 3.09 (s, 3H),b][1,4]diazepin-6(7H)-one 3.10-3.22 (m, 2H), 4.75-4.89 (m, 2H), 7.16 (brs, 1H), 7.33 (s, 4H), 7.74 (s, 1H). MS (ES+) 428, (ES−) 426. 9(S)-9-cyclopentyl-2-(1-(4- 1H NMR (DMSO-d6, 400 MHz)fluorophenyl)ethylamino)- δ 1.01 (s, 6H), 5,7,7-trimethyl-8,9- 1.38-1.49(m, 7H), 1.50-1.65 (m, dihydro-5H-pyrimido[4,5- 3H), 1.81-1.90 (m, 1H),b][1,4]diazepin-6(7H)-one 3.09 (s, 3H), 3.15-3.26 (m, 2H), 4.86 (br s,2H), 7.07-7.14 (m, 3H), 7.33-7.37 (m, 2H), 7.74 (s, 1H). MS (ES+) 412,(ES−) 410. 10 (S)-9-cyclopentyl-2-(1-(4- ¹H NMR (DMSO-d₆, 400 MHz):methoxyphenyl)ethylamino)- δ 1.02 (d, 6H), 5,7,7-trimethyl-8,9-1.35-1.65 (m, 11H), 3.09 (s, 3H), dihydro-5H-pyrimido[4,5- 3.23 (m, 2H),3.70 (s, 3H), b][1,4]diazepin-6(7H)-one 4.81 (br s, 1H), 4.98 (m, 1H),6.82 (m, 2H), 7.04 (m, 1H), 7.23 (m, 2H), 7.73 (1H, s). MS (ES+) 424,(ES−) 422. 11 (S)-9-cyclopentyl-2-(1-(3- ¹H NMR (DMSO-d₆, 400 MHz):methoxyphenyl)ethylamino)- δ 1.02 (d, 6H), 1.38 (d, 5,7,7-trimethyl-8,9-4H), 1.44-1.48 (m, 3H), dihydro-5H-pyrimido[4,5- 1.58-1.63 (m, 3H),1.80-1.90 (m, b][1,4]diazepin-6(7H)-one 1H), 3.09 (s, 3H), 3.11-3.28 (m,2H), 3.71 (s, 3H), 4.78-5.00 (m, 2H), 6.72-6.74 (m, 1H), 6.91 (s, 2H),7.18 (t, 2H), 7.74 (s, 1H). MS (ES+) 424, (ES−) 422. 12(S)-9-cyclopentyl-2-(1-(2- ¹H NMR (DMSO-d₆, 400 MHz):methoxyphenyl)ethylamino)- δ 1.00 (s, 6H), 1.31 (d, 5,7,7-trimethyl-8,9-3H), 1.24-1.64 (m, 8H), dihydro-5H-pyrimido[4,5- 1.79-1.85 (m, 1H), 3.09(s, 3H), b][1,4]diazepin-6(7H)-one 3.17-3.24 (m, 2H), 3.82 (s, 3H), 4.75(br s, 1H), 5.25 (br s, 1H), 6.84 (t, 1H), 6.94 (d, 1H), 7.13 (t, 1H),7.27 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H). MS (ES+) 424, (ES−) 423. 13(S)-9-cyclopentyl-5,7,7- ¹H NMR (DMSO-d₆, 400 MHz): trimethyl-2-(1-(2- δ0.99 (d, 6H), (trifluoromethyl)phenyl)ethylamino)- 1.18-1.28 (m, 2H),1.30-1.45 (m, 8,9-dihydro- 6H), 1.50-1.65 (m, 2H), 5H-pyrimido[4,5-1.68-1.78 (m, 1H), 3.08 (s, 3H), b][1,4]diazepin-6(7H)-one 3.18 (s, 2H),5.05 (br s, 1H), 5.30 (br s, 1H), 7.26 (d, 1H), 7.41 (d, 1H), 7.61-7.67(m, 2H), 7.75 (s, 1H), 7.80 (d, 1H). MS (ES+) 462, (ES−) 460. 14(S)-9-cyclopentyl-5,7,7- ¹H NMR (DMSO-d₆, 400 MHz): trimethyl-2-(1-(4- δ1.00 (d, 6H), nitrophenyl)ethylamino)- 1.20-1.45 (m, 7H), 1.50-1.70 (m,8,9-dihydro-5H- 3H), 1.75-1.85 (m, 1H), pyrimido[4,5- 3.08 (s, 3H),3.12-3.22 (m, 2H), b][1,4]diazepin-6(7H)-one 4.70 (br s, 1H), 4.95 (brs, 1H), 7.33 (s, 1H), 7.59 (d, 2H), 7.75 (s, 1H), 8.17 (d, 2H). MS (ES+)439, (ES−) 437. 15 (RS)-9-cyclopentyl-5,7,7- ¹H NMR (DMSO-d₆, 400 MHz):trimethyl-2-(1-(4- δ 1.00 (d, 6H), 1.41 (d,(methylsulfonyl)phenyl)ethylamino)- 6H), 1.51-1.71 (m, 3H), 8,9-dihydro-1.78-1.88 (m, 1H), 3.08 (s, 3H), 5H-pyrimido[4,5- 3.16 (s, 3H),3.18-3.24 (m, b][1,4]diazepin-6(7H)-one 2H), 4.90 (br s, 1H), 7.30 (brs, 1H), 7.58 (d, 2H), 7.75 (s, 1H), 7.84 (d, 2H). MS (ES+) 472, (ES−)470. 16 (RS)-2-(1-(biphenyl-4- ¹H NMR (DMSO-d₆, 400 MHz):yl)ethylamino)-9- δ 1.06 (d, 6H), cyclopentyl-5,7,7- 1.25-1.50 (m, 4H),1.60-1.72 (m, trimethyl-8,9-dihydro-5H- 4H), 1.90-2.00 (m, 1H),pyrimido[4,5- 3.13-3.32 (m, 5H), 4.95-5.05 (m, b][1,4]diazepin-6(7H)-one2H), 5.15 (br s, 1H), 7.34-7.37 (m, 1H), 7.46-7.50 (m, 4H), 7.51-7.62(m, 4H), 7.63 (s, H), 7.73 (s, 1H). MS (ES+) 470, (ES−) 468. 17(RS)-9-cyclopentyl-5,7,7- ¹H NMR (DMSO-d₆, 400 MHz): trimethyl-2-(1- δ0.95-1.00 (m, 2H), (naphthalen-1- 1.01 (d, 6H), 1.19-1.38 (m,yl)ethylamino)-8,9- 3H), 1.39-1.48 (m, 2H), dihydro-5H-pyrimido[4,5-1.58 (d, 4H), 3.05 (d, 1H), b][1,4]diazepin-6(7H)-one 3.05-3.15 (m, 2H),3.15 (s, 3H), 4.55 (br s, 1H), 5.35 (br s, 1H), 5.75-5.82 (m, 1H),7.41-7.59 (m, 3H), 7.62 (d, 1H), 7.70-7.80 (m, 2H), 7.91 (d, 1H), 8.20(d, 1H). MS (ES+) 444, (ES−) 442. 18 (RS)-9-cyclopentyl-5,7,7- ¹H NMR(DMSO-d₆, 400 MHz): trimethyl-2-(1-(pyridin-3- δ 1.35-1.51 (m, 8H),yl)ethylamino)-8,9- 1.51-1.75 (m, 2H), dihydro-5H-pyrimido[4,5-1.78-1.84 (m, 1H), 3.10 (s, 3H), b][1,4]diazepin-6(7H)-one 3.11-3.25 (m,2H), 4.89-4.92 (m, 2H), 7.22 (s, 1H), 7.28-7.31 (m, 1H), 7.71-7.75 (m,2H), 8.38 (m, 1H), 8.54 (s, 1H). MS (ES+) 395, (ES−) 393. 19(RS)-9-cyclopentyl-5,7,7- ¹H NMR (DMSO-d₆, 400 MHz):trimethyl-2-(1-(pyridin-4- δ 1.00 (s, 6H), 1.29 (d, yl)ethylamino)-8,9-3H), 1.28-1.40 (m, 4H), dihydro-5H-pyrimido[4,5- 1.54-1.67 (m, 3H),1.74-1.88 (m, b][1,4]diazepin-6(7H)-one 1H), 3.09 (s, 3H), 3.20-3.27 (m,2H), 4.80-4.90 (br s, 2H), 7.25 (br s, 1H), 7.31 (d, 2H), 7.75 (s, 1H),8.44 (d, 2H). MS (ES+) 395, (ES−) 393. 20 (RS)-9-cyclopentyl-2-(1- ¹HNMR (DMSO-d₆, 400 MHz): (furan-2-yl)ethylamino)- δ 1.05 (s, 6H), 1.42(d, 5,7,7-trimethyl-8,9- 3H), 1.48-1.59 (m, 4H),dihydro-5H-pyrimido[4,5- 1.61-1.74 (m, 3H), 1.79-1.87 (m,b][1,4]diazepin-6(7H)-one 1H), 3.12 (s, 3H), 3.27 (s, 2H), 4.99-5.15 (brm, 2H), 6.13 (s, 1H), 6.34 (s, 1H), 6.89 (br d, 1H), 7.51 (s, 1H), 7.78(s, 1H). MS (ES+) 384. 21 (RS)-9-cyclopentyl-2-(1- ¹H NMR (DMSO-d₆, 400MHz): (3,4- δ 1.02 (d, 6H), 1.37 (d, dimethoxyphenyl)ethylamino)- 3H),1.40-1.72 (m, 7H), 5,7,7-trimethyl-8,9- 1.80-1.88 (m, 1H), 3.09 (s, 3H),dihydro-5H-pyrimido[4,5- 3.17-3.27 (m, 2H), 3.70 (s,b][1,4]diazepin-6(7H)-one 3H), 3.72 (s, 3H), 4.84-5.03 (br m, 2H), 6.83(s, 2H), 6.97 (s, 1H), 7.02 (br s, 1H), 7.74 (s, 1H). MS (ES+) 454,(ES−) 452. 22 (RS)-9-cyclopentyl-5,7,7- ¹H NMR (DMSO-d₆, 400 MHz)trimethyl-2-(1-(4- δ 1.00 (s, 6H), 1.39 (d,(trifluoromethoxy)phenyl)ethylamino)- 3H), 1.34-1.46 (m, 4H),8,9-dihydro- 1.50-1.72 (m, 3H), 1.74-1.84 (m, 5H-pyrimido[4,5- 1H), 3.09(s, 3H), b][1,4]diazepin-6(7H)-one 3.14-3.21 (m, 2H), 4.80-4.96 (br m,2H), 7.20 (br s, 1H), 7.27 (d, 2H), 7.43 (d, 2H), 7.75 (s, 1H). MS (ES+)478 (ES−) 476. 23 (R)—N-((S)-1-(4- ¹H NMR (CDCl₃, 400 MHz):bromophenyl)ethyl)-5- δ 0.8-0.9 (m, 3H), 1.6-1.9 (m,cyclopentyl-4-ethyl-4,5- 11H), 2.1-2.15 (m, 3H), dihydro- 4.18-4.25 (m,1H), 4.9-5.0 (m, [1,2,4]triazolo[4,3- 1H), 5.2-5.25 (m, 1H),f]pteridin-7-amine 7.25 (d, 2H), 7.45 (d, 2H), 8.9 (s, [from(6R)-3-chloro-5- 1H), 8.98-9.08 (m, 2H). cyclopentyl-6-ethyl-6H- MS(ES+) 470, (ES−) 468. imidazo[1,2-f]pteridine, synthesized as describedin WO 2007/120752] 24 (R)-5-cyclopentyl-4-ethyl- ¹H NMR (CDCl₃, 400MHz): N-((S)-1-phenylethyl)-4,5- δ 0.8-0.9 (m, 3H), 1.5-2.2 (m, dihydro-14H), 4.2-4.3 (m, 1H), [1,2,4]triazolo[4,3- 5.0-5.1 (m, 2H), 5.38-5.45(m, f]pteridin-7-amine 1H), 7.2-7.4 (m, 5H), 8.05 (s, 1H), 8.5 (s, 1H).MS (ES+) 390, (ES−) 388. 25 (R)-8-cyclopentyl-7-ethyl- ¹H NMR (CDCl₃,400 MHz) 5-methyl-2-((S)-1- δ 0.8-0.9 (m, 3H), 1.5-1.9 (m,phenylethylamino)-7,8- 12H), 2.0-2.1 (m, 1H), dihydropteridin-6(5H)-one3.25 (s, 3H), 4.1-4.2 (m, 2H), [from (R)-2-chloro-8- 5.0-5.1 (m, 1H),5.18-5.25 (m, cyclopentyl-7-ethyl-5- 1H), 7.2-7.4 (m, 5H), 7.5 (s,methyl-7,8- 1H); MS (ES+) 380, (ES−) dihydropteridin-6(5H)- 378. one,synthesized as described in US 2004/176380] 27(R,S)-9-cyclopentyl-5,7,7- ¹H NMR (DMSO-d₆, 400 MHz): trimethyl-2-(1-(2-δ 1.05 (d, 6H), 1.43 (d, methylthiazol-4- 3H), 1.42-1.55 (m, 4H),yl)ethylamino)-8,9- 1.58-1.67 (m, 3H), 1.74-1.83 (m,dihydro-5H-pyrimido[4,5- 1H), 2.61 (s, 3H), 3.11 (s,b][1,4]diazepin-6(7H)-one 3H), 3.25-3.28 (m, 2H), 5.04 (br s, 2H), 6.87(br s, 1H), 7.05 (s, 1H), 7.77 (s, 1H). MS (ES+) 415, (ES−) 413. 28(S)-9-cyclopentyl-5,7,7- ¹H NMR (DMSO-d₆, 400 MHz): trimethyl-2-(1-(3- δ0.87 (d, 6H), 1.28 (d, (trifluoromethyl)phenyl)ethylamino)- 3H),1.25-1.60 (m, 7H), 8,9-dihydro- 1.65-1.72 (m, 1H), 2.96 (s, 3H),5H-pyrimido[4,5- 3.02-3.12 (m, 2H), 4.82 (br s,b][1,4]diazepin-6(7H)-one 2H), 7.15 (br s, 1H), 7.40 (d, 2H), 7.50-7.53(m, 2H), 7.62 (s, 1H). MS (ES+) 462, (ES−) 460. 29(R,S)-9-cyclopentyl-2-(1- ¹H NMR (DMSO-d₆, 400 MHz): (2- δ 1.00 (s, 6H),1.38 (d, fluorophenyl)ethylamino)- 3H), 1.30-1.50 (m, 4H),5,7,7-trimethyl-8,9- 1.52-1.65 (m, 3H), 1.77-1.83 (m,dihydro-5H-pyrimido[4,5- 1H), 3.09 (s, 3H), b][1,4]diazepin-6(7H)-one3.14-3.25 (m, 2H), 4.89 (br s, 1H), 5.19 (br s, 1H), 7.10-7.13 (m, 2H),7.19-7.22 (m, 2H), 7.39-7.42 (m, 1H), 7.75 (s, 1H). MS (ES+) 412, (ES−)410. 30 (R,S)-9-cyclopentyl-2-(1- ¹H NMR (DMSO-d₆, 400 MHz): (3,5- δ1.01 (s, 6H), 1.38 (d, difluorophenyl)ethylamino)- 3H), 1.37-1.50 (m,4H), 5,7,7-trimethyl-8,9- 1.54-1.65 (m, 3H), 1.78-1.88 (m,dihydro-5H-pyrimido[4,5- 1H), 3.10 (s, 3H), b][1,4]diazepin-6(7H)-one3.16-3.25 (m, 2H), 4.09 (br s, 2H), 6.97-7.04 (m, 3H), 7.21 (br s, 1H),7.76 (s, 1H). MS (ES+) 430, (ES−) 428. 31 (S)-9-cyclopentyl-5,7,7- ¹HNMR (DMSO-d₆, 400 MHz): trimethyl-2-(1-(4- δ 1.00 (d, 6H), 1.41 (d,(trifluoromethyl)phenyl)ethylamino)- 3H), 1.15-1.47 (m, 4H),8,9-dihydro- 1.39-1.68 (m, 3H), 1.73-1.82 (m, 5H-pyrimido[4,5- 1H), 3.09(s, 3H), b][1,4]diazepin-6(7H)-one 3.15-3.26 (m, 2H), 4.89 (br s, 2H),7.26 (br s, 1H), 7.54 (d, 2H), 7.65 (d, 2H), 7.75 (s, 1H). MS (ES+) 462,(ES−) 460. 32 (S)-2-(1-(3,5- ¹H NMR (DMSO-d₆, 400 MHz):bis(trifluoromethyl)phenyl)ethylamino)- δ 0.96 (s, 3H), 1.01 (s, 9- 3H),1.45 (d, 3H), cyclopentyl-5,7,7- 1.12-1.60 (m, 7H), 1.75-1.83 (m, 1H),trimethyl-8,9-dihydro-5H- 3.09 (s, 3H), 3.20 (s, 2H), pyrimido[4,5- 4.81(br s, 1H), 5.07 (br b][1,4]diazepin-6(7H)-one s, 1H), 7.37 (br s, 1H),7.78 (s, 1H), 7.92 (s, 1H), 8.02 (s, 2H). MS (ES+) 530, (ES−) 528. 33(R)-4-ethyl-5-phenyl-N- ¹H NMR (DMSO-d₆, 400 MHz):((S)-1-phenylethyl)-4,5- δ 0.73 (t, 3H), 1.30 (d, dihydro- 3H),1.66-1.76 (m, 1H), [1,2,4]triazolo[4,3- 1.91-1.94 (m, 1H), 4.49 (br s,1H), f]pteridin-7-amine 5.49 (br s, 1H), 6.69 (br s, [from(6R)-3-chloro-6- 1H), 7.04 (br s, 3H), 7.44 (d, ethyl-5-phenyl-6H- 5H),7.56 (s, 2H), 8.46 (s, imidazo[1,2-f]pteridine, 1H), 9.21 (s, 1H); MS(ES+) synthesized as described 398, (ES−) 396. in WO2007120752] 345-cyclopentyl-4-(R)-ethyl- ¹H NMR (CDCl₃, 400 MHz): N-((S)1-(4-(4- δ0.85-0.95 (m, 3H), methylpiperazin-1- 1.3-1.4 (m, 3H), 1.45-1.8 (m,14H), yl)phenyl)ethyl)-4,5- 1.9-2.0 (m, 1H), 2.0-2.1 (m, dihydro- 1H),2.3-2.4 (m, 2H), [1,2,4]triazolo[4,3- 2.6-2.7 (m, 2H), 3.2-3.3 (m, 2H),f]pteridin-7-amine 4.3-4.4 (m, 1H), 5.0-5.1 (m, 2H), 5.25-5.35 (m, 1H),6.9-6.96 (m, 1H), 7.25-7.35 (m, 2H), 8.1 (s, 1H), 8.5 (s, 1H). MS (ES+)488.1 (ES−) 488.1 35 5-cyclopentyl-4-(R)-ethyl- ¹H NMR (CDCl₃, 400 MHz):N-((S)1-(4-(piperazin-1- δ 0.67-0.71 (m, 3H), 1.44 (m,yl)phenyl)ethyl)-4,5- 3H), 1.42-1.92 (m, 11H), dihydro- 3.22-3.26 (m,8H), 4.95 (b s, [1,2,4]triazolo[4,3- 1H), 5.15 (br s, 1H),f]pteridin-7-amine 6.92-6.96 (m, 2H), 7.22-7.24 (m, 2H), 8.42 (br s,1H), 8.66 (m, 2H), 9.16 (s, 1H). MS (ES+) 474.1

Example 6(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one

(S)-2-(1-(4-Bromophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(100 mg, 0.2117 mmol), 1-methylpiperazine (84.82 mg, 93.93 μL, 0.8468mmol), di-tert-butyl-(2-phenylphenyl)phosphane (6.317 mg, 0.02117 mmol)and K₃PO₄ (89.87 mg, 0.4234 mmol) were taken in up DME (2 mL) anddegassed using cycles of vacuum and nitrogen. Pd₂DBA₃ (19.39 mg, 0.02117mmol) was added and the reaction mixture was further degassed and thenheated at 100° C. in a sealed tube for 4 hours and then allowed to coolto the ambient temperature. The reaction mixture was then diluted withethyl acetate (5 mL) and filtered. The filtrate was concentrated invacuo and the residue purified by mass directed HPLC and the combinedproduct fractions passed through a bicarbonate cartridge and lypholizedto give the title compound as a white solid (9.9 mg, 10% yield).

¹H NMR (DMSO-d6, 400 MHz): δ 1.02 (d, 6H), 1.35 (d, 3H), 1.36-1.56 (m,4H), 1.57-1.70 (m, 3H), 1.79-1.88 (m, 1H), 2.20 (s, 3H), 2.40-2.43 (m,4H), 3.04-3.06 (m, 4H), 3.09 (s, 3H), 3.24-3.29 (m, 2H), 4.78-4.99 (brm, 2H), 6.83 (d, 2H), 7.03 (br s, 1H), 7.16 (d, 2H), 7.73 (s, 1H).

MS (ES+) 492, (ES−) 490.

Example 26(S)-9-cyclopentyl-2-(1-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]-diazepin-6(7H)-one

Into an oven dried Schlenk tube dried under Argon was added(S)-2-(1-(4-bromophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one(100 mg, 0.2096 mmol), CuI (1.996 mg, 0.01048 mmol),N,N-diethyl-2-hydroxy-benzamide (8.101 mg, 0.04192 mmol) and K₃PO₄(88.98 mg, 0.4192 mmol). The tube was evacuated and re-filled with Argon(three times), and N,N′,N′-trimethylethane-1,2-diamine (32.12 mg, 40.87μL, 0.3144 mmol) in DMF (1 mL) was added and the reaction mixture washeated to 90° C. for 96 h. Additional CuI (1.996 mg, 0.01048 mmol),N,N-diethyl-2-hydroxy-benzamide (8.101 mg, 0.04192 mmol) andN,N′,N′-trimethylethane-1,2-diamine (214.2 mg, 272.5 μL, 2.096 mmol)were added to the tube and the tube was re-charged with argon and heatedto 90° C. overnight. The reaction mixture was then cooled to the ambienttemperature and diluted with ethyl acetate (5 mL), water (5 mL) andammonium hydroxide (0.2 mL). The aqueous layer was extracted with ethylacetate (four times, 5 mL each), dried with MgSO₄, filtered andconcentrated in vacuo. The crude product was purified by mass directedHPLC and product fractions combined and passed through a bicarbonatecartridge and lyophilized to give the title compound as a white solid(18.5 mg, 17% yield).

¹H NMR (DMSO-d₆, 400 MHz): δ 1.04 (d, 6H), 1.34 (d, 3H), 1.37-1.72 (m,7H), 1.79-1.95 (m, 1H), 2.21 (s, 6H), 2.30-2.34 (m, 2H), 2.84 (s, 3H),3.09 (s, 3H), 3.24-3.28 (m, 2H), 3.34-3.42 (m, 2H), 4.75 (br s, 1H),5.04 (br s, 1H), 6.58 (d, 2H), 6.94 (br s, 1H), 7.13 (d, 2H), 7.73 (s,1H).

MS (ES+) 494.

Example 12 PLK Assays

The compounds of the present invention are evaluated as inhibitors ofhuman PLK kinase using the following assays.

PLK1 Inhibition Assay I:

Compounds were screened for their ability to inhibit PLK1 using aradioactive-phosphate incorporation assay. Assays were carried out in amixture of 25 mM HEPES (pH 7.5), 10 mM MgCl₂, and 1 mM DTT. Finalsubstrate concentrations were 350 μM [γ-33P]ATP (136 mCi 33P ATP/mmolATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 450 μM peptide(KKKISDELMDATFADQEAK) [SEQ. ID:1]. Assays were carried out at 25° C. inthe presence of 2 nM PLK1. An assay stock buffer solution was preparedcontaining all of the reagents listed above, with the exception of ATPand the test compound of interest. 30 μL of the stock solution wasplaced in a 96 well plate followed by addition of 2 μL of DMSO stockcontaining serial dilutions of the test compound (typically startingfrom a final concentration of 10 μM with 2-fold serial dilutions) induplicate (final DMSO concentration 5%). The plate was pre-incubated for10 minutes at 25° C. and the reaction initiated by addition of 8 μL[γ-33P]ATP (final concentration 350 μM).

The reaction was stopped after 240 minutes by the addition of 100 μL0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-wellplate (Millipore, Cat No. MAPHN0B50) was pretreated with 100 μL 0.1 Mphosphoric acid prior to the addition of 125 μL of the stopped assaymixture. The plate was washed with 4×200 μL 0.1 M phosphoric acid. Afterdrying, 100 μL Optiphase ‘SuperMix’ liquid scintillation cocktail(Perkin Elmer) was added to the well prior to scintillation counting(1450 Microbeta Liquid Scintillation Counter, Wallac).

After removing mean background values for all of the data points,Ki(app) data were calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

PLK1 Inhibition Assay II:

Compounds were screened for their ability to inhibit PLK1 using aradioactive-phosphate incorporation assay. Assays were carried out in amixture of 25 mM HEPES (pH 7.5), 10 mM MgCl₂, 0.1% BSA, and 2 mM DTT.Final substrate concentrations were 150 μM [γ-33P]ATP (115 mCi 33PATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 300 μMpeptide (KKKISDELMDATFADQEAK) [SEQ. ID:2]. Assays were carried out at25° C. in the presence of 4 nM PLK1. An assay stock buffer solution wasprepared containing all of the reagents listed above, with the exceptionof ATP and the test compound of interest. 30 μL of the stock solutionwas placed in a 96 well plate followed by addition of 2 μL of DMSO stockcontaining serial dilutions of the test compound (typically startingfrom a final concentration of 10 μM with 2-fold serial dilutions) induplicate (final DMSO concentration 5%). The plate was pre-incubated for10 minutes at 25° C. and the reaction initiated by addition of 8 μL[γ-33P]ATP (final concentration 150 μM).

The reaction was stopped after 90 minutes by the addition of 100 μL 0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-well plate(Millipore, Cat No. MAPHN0B50) was pretreated with 100 μL 0.1 Mphosphoric acid prior to the addition of 125 μL of the stopped assaymixture. The plate was washed with 4×200 μL 0.1 M phosphoric acid. Afterdrying, 100 μL Optiphase ‘SuperMix’ liquid scintillation cocktail(Perkin Elmer) was added to the well prior to scintillation counting(1450 Microbeta Liquid Scintillation Counter, Wallac).

After removing mean background values for all of the data points,Ki(app) data were calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

The compounds of this invention demonstrated inhibitory effect ofdifferent levels on PLK1. In some instances, the compounds of thisinvention demonstrated PLK1 inhibition at concentrations of less than100 nM. In some other instances, the compounds of this inventiondemonstrated PLK1 inhibition at concentrations of between 1 nM and 10nM.

PLK2 Inhibition Assay:

Compounds were screened for their ability to inhibit PLK2 using aradioactive-phosphate incorporation assay. Assays were carried out in amixture of 25 mM HEPES (pH 7.5), 10 mM MgCl₂, 0.1% BSA, and 2 mM DTT.Final substrate concentrations were 200 μM [γ-33P]ATP (57 mCi 33PATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 300 μMpeptide (KKKISDELMDATFADQEAK) [SEQ ID:3]. Assays were carried out at 25°C. in the presence of 25 nM PLK2. An assay stock buffer solution wasprepared containing all of the reagents listed above, with the exceptionof ATP and the test compound of interest. 30 μL of the stock solutionwas placed in a 96 well plate followed by addition of 2 μl of DMSO stockcontaining serial dilutions of the test compound (typically startingfrom a final concentration of 10 μM with 2-fold serial dilutions) induplicate (final DMSO concentration 5%). The plate was pre-incubated for10 minutes at 25° C. and the reaction initiated by addition of 8 μL[γ-33P]ATP (final concentration 200 μM).

The reaction was stopped after 90 minutes by the addition of 100 μL 0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-well plate(Millipore, Cat No. MAPHN0B50) was pretreated with 100 μL 0.2Mphosphoric acid prior to the addition of 125 μl, of the stopped assaymixture. The plate was washed with 4×200 μL 0.2 M phosphoric acid. Afterdrying, 100 μL Optiphase ‘SuperMix’ liquid scintillation cocktail(Perkin Elmer) was added to the well prior to scintillation counting(1450 Microbeta Liquid Scintillation Counter, Wallac).

After removing mean background values for all of the data points,Ki(app) data were calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

PLK3 Inhibition Assay:

Compounds were screened for their ability to inhibit PLK3 using aradioactive-phosphate incorporation assay. Assays were carried out in amixture of 25 mM HEPES (pH 7.5), 10 mM MgCl2, and 1 mM DTT. Finalsubstrate concentrations were 75 μM [γ-33P]ATP (60 mCi 33P ATP/mmol ATP,Amersham Pharmacia Biotech/Sigma Chemicals) and 10 μM peptide (SAM68protein Δ332-443). Assays were carried out at 25° C. in the presence of5 nM PLK3 (S38-A340). An assay stock buffer solution was preparedcontaining all of the reagents listed above, with the exception of ATPand the test compound of interest. 30 μL of the stock solution wasplaced in a 96 well plate followed by addition of 2 μL of DMSO stockcontaining serial dilutions of the test compound (typically startingfrom a final concentration of 10 μM with 2-fold serial dilutions) induplicate (final DMSO concentration 5%). The plate was pre-incubated for10 minutes at 25° C. and the reaction initiated by addition of 8 μL[γ-33P]ATP (final concentration 75 μM).

The reaction was stopped after 60 minutes by the addition of 100 μL 0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-well plate(Millipore, Cat No. MAPHN0B50) was pretreated with 100 μL 0.2Mphosphoric acid prior to the addition of 125 μL of the stopped assaymixture. The plate was washed with 4×200 μL 0.2 M phosphoric acid. Afterdrying, 100 μL Optiphase ‘SuperMix’ liquid scintillation cocktail(Perkin Elmer) was added to the well prior to scintillation counting(1450 Microbeta Liquid Scintillation Counter, Wallac).

After removing mean background values for all of the data points,Ki(app) data were calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

PLK4 Inhibition Assay:

Compounds are screened for their ability to inhibit PLK4 using aradioactive-phosphate incorporation assay. Assays are carried out in amixture of 8 mM MOPS (pH 7.5), 10 mM MgCl₂, 0.1% BSA and 2 mM DTT. Finalsubstrate concentrations are 15 μM [γ-33P]ATP (227 mCi 33P ATP/mmol ATP,Amersham Pharmacia Biotech/Sigma Chemicals) and 300 μM peptide(KKKMDATFADQ) [SEQ ID:4]. Assays are carried out at 25° C. in thepresence of 25 nM PLK4. An assay stock buffer solution is preparedcontaining all of the reagents listed above, with the exception of ATPand the test compound of interest. 30 μL of the stock solution is placedin a 96 well plate followed by addition of 2 μL of DMSO stock containingserial dilutions of the test compound (typically starting from a finalconcentration of 10 μM with 2-fold serial dilutions) in duplicate (finalDMSO concentration 5%). The plate is pre-incubated for 10 minutes at 25°C. and the reaction initiated by addition of 8 μL [γ-33P]ATP (finalconcentration 15 μM).

The reaction is stopped after 180 minutes by the addition of 100 μL0.14M phosphoric acid. A multiscreen phosphocellulose filter 96-wellplate (Millipore, Cat No. MAPHN0B50) is pretreated with 100 μL 0.2 Mphosphoric acid prior to the addition of 125 μL of the stopped assaymixture. The plate is washed with 4×200 μL 0.2 M phosphoric acid. Afterdrying, 100 μL Optiphase ‘SuperMix’ liquid scintillation cocktail(Perkin Elmer) is added to the well prior to scintillation counting(1450 Microbeta Liquid Scintillation Counter, Wallac).

After removing mean background values for all of the data points,Ki(app) data are calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prismversion 3.0cx for Macintosh, GraphPad Software, San Diego Calif., USA).

The compounds of this invention demonstrated inhibitory effect ofdifferent levels on PLK2, PLK3, or PLK4.

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein Y is O or NR⁹; R¹is aryl or heteroaryl; R² is H, alkyl, or cycloalkyl; each of R³ and R⁴is independently H, alkyl, cycloalkyl, aryl, or heteroaryl; or R³ andR⁴, together with the carbon atom to which they are attached, form acycloalkyl; each of R⁵ and R⁶ is independently H, alkyl, cycloalkyl,aryl, or heteroaryl; R⁷ is H, alkyl, cycloalkyl, aryl, heteroaryl, orheterocyclyl; R⁸ is alkyl; R⁹ is H or alkyl; or R² and R⁹, together withthe atoms to which they are attached, optionally form a 5- to 8-memberedmonocyclic ring containing additional 0 to 2 hetero atoms eachindependently selected from O, N, and S, wherein said monocyclic ring isoptionally substituted with 0 to 4 groups each independently beingalkyl, halo, alkoxy, or hydroxy; and q is 0 or
 1. 2. The compound ofclaim 1, wherein R² is alkyl.
 3. The compound of claim 2, wherein R² ismethyl.
 4. The compound of claim 1, wherein Y is O.
 5. The compound ofclaim 1, wherein each of R³ and R⁴ is independently H or alkyl.
 6. Thecompound of claim 5, wherein each of R³ and R⁴ is independently H,methyl, or ethyl.
 7. The compound of claim 1, wherein R⁷ is alkyl orcycloalkyl.
 8. The compound of claim 7, wherein R⁷ is cycloalkyl.
 9. Thecompound of claim 8, wherein R⁷ is cyclopentyl.
 10. The compound ofclaim 1, wherein q is
 1. 11. The compound of claim 10, wherein each ofR⁵ and R⁶ is independently H or alkyl.
 12. The compound of claim 11,wherein each of R⁵ and R⁶ is H.
 13. The compound of claim 1, wherein R⁸is optionally substituted alkyl.
 14. The compound of claim 13, whereinR⁸ is methyl, ethyl, methoxymethyl, methoxyethyl, hydroxymethyl, orhydroxyethyl.
 15. The compound of claim 14, wherein R⁸ is methyl. 16.The compound of claim 15, wherein the carbon atom to which R⁸ isattached is in the S configuration.
 17. The compound of claim 1, whereinR¹ is optionally substituted phenyl, optionally substituted napthyl,optionally substituted pyridyl, optionally substituted furanyl oroptionally substituted thiazolyl.
 18. The compound of claim 17, whereinR¹ is phenyl optionally substituted with 1 to 3 substituents eachindependently selected from the group consisting of alkyl, halo, amino,alkoxy, haloalkyl, alkylsulfonyl, nitro, phenyl, 1-piperazinyl, and4-alkylpiperazin-1-yl.
 19. The compound of claim 18, wherein R¹ isphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl,2-methoxyphenyl, 3,4-dimethoxyphenyl, 4-(trifluoromethoxy)phenyl,2-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl,3-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl,4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 2-fluorophenyl,3,5-difluorophenyl, 4-(4-methylpiperazin-1-yl)phenyl,4-(piperazin-1-yl)phenyl,4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl, 4-nitrophenyl,4-(methylsulfonyl)phenyl, biphenyl-4-yl, naphthalenyl, 3-pyridinyl,2-pyridinyl, 4-pyridinyl, 2-furanyl, 4-thiazolyl, or2-methylthiazol-4-yl.
 20. The compound of claim 1, wherein the compoundis represented by Formula Ia.


21. The compound of claim 1, wherein the compound is9-cyclopentyl-5,7,7-trimethyl-2-(1-phenylethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-phenylpropylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-2-(2-methoxy-1-phenylethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-2-(2-hydroxy-1-phenylethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;2-(1-(4-bromophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(piperazin-1-yl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-2-(1-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-p-tolylethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;2-(1-(4-chlorophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-2-(1-(4-fluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-2-(1-(2-fluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-2-(1-(3,5-difluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-2-(1-(4-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-2-(1-(3-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-2-(1-(2-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-2-(1-(3,4-dimethoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(trifluoromethoxy)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-(3-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;2-(1-(3,5-bis(trifluoromethyl)phenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-(2-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-nitrophenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(methylsulfonyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;2-(1-(biphenyl-4-yl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-(naphthalen-1-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-3-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-2-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;9-cyclopentyl-2-(1-(furan-2-yl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;or9-cyclopentyl-5,7,7-trimethyl-2-(1-(2-methylthiazol-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one.22. The compound of claim 1, wherein q is
 0. 23. The compound of claim22, wherein each of R³ and R⁴ is independently H or alkyl.
 24. Thecompound of claim 23, wherein each of R³ and R⁴ is independently H,methyl, or ethyl.
 25. The compound of claim 24, wherein R³ is ethyl andR⁴ is H.
 26. The compound of claim 25, wherein the carbon atom to whichR³ and R⁴ are attached is in the R configuration.
 27. The compound ofclaim 22, wherein R¹ is optionally substituted aryl or optionallysubstituted heteroaryl.
 28. The compound of claim 27, wherein R¹ isphenyl optionally substituted with 1 to 3 of alkyl, halo, amino, alkoxy,haloalkyl, alkylsulfonyl, nitro, phenyl, 1-piperazinyl, or4-methylpiperazin-1-yl.
 29. The compound of claims 22, wherein R⁸ isoptionally substituted alkyl or optionally substituted cycloalkyl. 30.The compound of claim 29, wherein R⁸ is optionally substituted alkyl.31. The compounds of claim 30, wherein R⁸ is methyl, ethyl,methoxymethyl, methoxyethyl, hydroxymethyl, or hydroxyethyl.
 32. Thecompound of claim 31, wherein R⁸ is methyl.
 33. The compound of claim32, wherein the carbon to which R⁸ is attached is of the Sconfiguration.
 34. The compound of claim 22, wherein the compound isrepresented by Formula Ib.


35. The compound of claim 1, wherein the compound is8-cyclopentyl-7-ethyl-5-methyl-2-(1-phenylethylamino)-7,8-dihydropteridin-6(5H)-one.36. The compound of claim 1, wherein Y is NR⁹.
 37. The compound of claim36, wherein R² and R⁹, together with the atoms to which they areattached, form a 5- to 8-membered monocyclic ring containing additional0-2 hetero atoms each independently selected from O, N, and S, whereinsaid monocyclic ring is optionally substituted with 0 to 4 groups eachindependently being halo or alkyl.
 38. The compound of claim 36, whereinq is
 0. 39. The compound of claim 36, wherein each of R³ and R⁴ isindependently H or alkyl.
 40. The compound of claim 39, wherein R³ isethyl and R⁴ is H.
 41. The compound of claim 36, wherein R⁷ iscycloalkyl.
 42. The compound of claim 41, wherein R⁷ is cyclopentyl. 43.The compound of claim 36, wherein R⁷ is aryl.
 44. The compound of claim43, wherein R⁷ is phenyl.
 45. The compound of claim 36, wherein R¹ isoptionally substituted aryl or optionally substituted heteroaryl. 46.The compound of claim 45, wherein R¹ is optionally substituted aryl. 47.The compound of claim 46, wherein R¹ is phenyl, p-bromophenyl, or4-methylpiperazin-1-yl.
 48. The compound of claim 36, wherein R⁸ isalkyl.
 49. The compound of claim 48, wherein R⁸ is methyl, ethyl,methoxymethyl, methoxyethyl, hydroxymethyl, or hydroxyethyl.
 50. Thecompound of claim 49, wherein R⁸ is methyl.
 51. The compound of claim50, wherein the carbon to which R⁸ is attached is of the Sconfiguration.
 52. The compound of claim 36, wherein the compound isrepresented by Formula Ic:


53. The compound of claim 1, wherein the compound is5-cyclopentyl-4-ethyl-N-(1-phenylethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-N-(1-(4-bromophenyl)ethyl)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;5-cyclopentyl-4-ethyl-N-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;5-cyclopentyl-4-ethyl-N-(1-(4-(piperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;or4-ethyl-5-phenyl-N-(1-phenylethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine.54. The compound of claim 1, wherein the compound is5-cyclopentyl-4-ethyl-N-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine,or5-cyclopentyl-4-ethyl-N-(1-(4-(piperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine.55. The compound of claim 1, wherein the compound is:(R)-5-cyclopentyl-4-ethyl-N—((S)-1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;or(R)-5-cyclopentyl-4-ethyl-N—((S)-1-(4-(piperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine.56. The compound of claim 1, wherein the compound is:(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-phenylethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-phenylpropylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(R)-9-cyclopentyl-2-(2-methoxy-1-phenylethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(R)-9-cyclopentyl-2-(2-hydroxy-1-phenylethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-2-(1-(4-bromophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-p-tolylethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-2-(1-(4-chlorophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-9-cyclopentyl-2-(1-(4-fluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-9-cyclopentyl-2-(1-(4-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-9-cyclopentyl-2-(1-(3-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-9-cyclopentyl-2-(1-(2-methoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(2-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-nitrophenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(methylsulfonyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(RS)-2-(1-(biphenyl-4-yl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(naphthalen-1-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-3-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(pyridin-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(RS)-9-cyclopentyl-2-(1-(furan-2-yl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(RS)-9-cyclopentyl-2-(1-(3,4-dimethoxyphenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(RS)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(trifluoromethoxy)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(R)—N—((S)-1-(4-bromophenyl)ethyl)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;(R)-5-cyclopentyl-4-ethyl-N—((S)-1-phenylethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;(R)-8-cyclopentyl-7-ethyl-5-methyl-2-((S)-1-phenylethylamino)-7,8-dihydropteridin-6(5H)-one;(S)-9-cyclopentyl-2-(1-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(R,S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(2-methylthiazol-4-yl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(3-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(R,S)-9-cyclopentyl-2-(1-(2-fluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(R,S)-9-cyclopentyl-2-(1-(3,5-difluorophenyl)ethylamino)-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-9-cyclopentyl-5,7,7-trimethyl-2-(1-(4-(trifluoromethyl)phenyl)ethylamino)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(S)-2-(1-(3,5-bis(trifluoromethyl)phenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one;(R)-4-ethyl-5-phenyl-N—((S)-1-phenylethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;(R)—N—((S)-1-(4-bromophenyl)ethyl)-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;(R)-5-cyclopentyl-4-ethyl-N—((S)-1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine;or(R)-5-cyclopentyl-4-ethyl-N—((S)-1-(4-(piperazin-1-yl)phenyl)ethyl)-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-amine.57. A composition comprising a compound of any of claims 1 to 56, and apharmaceutically acceptable carrier, adjuvant, or vehicle.
 58. A methodof inhibiting protein kinase in a patient comprising administering tosaid patient in need thereof a pharmaceutically effective amount of acompound of any of claims 1 to 56 or a composition of claim
 57. 59. Themethod of claim 58, wherein the protein kinase is a PLK.
 60. The methodof claim 59, wherein said protein kinase is PLK1.
 61. A method ofinhibiting protein kinase in a biological sample comprising contactingsaid biological sample with a pharmaceutically effective amount of acompound of any of claims 1 to 56 or a composition of claim
 57. 62. Themethod of claim 61, wherein the protein kinase is a PLK.
 63. The methodof claim 62, wherein the protein kinase is PLK1.
 64. A method oftreating a proliferative disorder, a neurodegenerative disorder, anautoimmune disorder, an inflammatory disorder, or an immunologicallymediated disorder in a patient, comprising the step of administering toa patient in need thereof a pharmaceutically effective amount of acompound of any of claims 1 to 56 or a composition of claim
 57. 65. Themethod of claim 64, further comprising administering to the patient achemotherapeutic agent, an anti-proliferative agent, ananti-inflammatory agent, an immunomodulatory agent, an immunosuppressiveagent, a neurotrophic factor, an agent for treating cardiovasculardisease, an agent for treating destructive bone disorder, an agent fortreating liver disease, an anti-viral agent, an agent for treating blooddisorder, an agent for treating diabetes, or an agent for treatingimmunodeficiency disorder.
 66. A method of treating melanoma, myeloma,leukemia, lymphoma, neuroblastoma, colon cancer, breast cancer, gastriccancer, ovarian cancer, cervical cancer, lung cancer, central nervoussystem cancer, renal cancer, prostate cancer, bladder cancer, orpancreatic cancer, in a patient, comprising administering to the patientin need thereof a pharmaceutically effective amount of a compound of anyof claims 1 to 56 or a composition of claim
 57. 67. A method of treatingcancer in a patient, comprising administering to the patient in needthereof a pharmaceutically effective amount of a compound of any ofclaims 1 to 56 or a composition of claim
 57. 68. The method of claim 67,wherein the method comprises disrupting mitosis of the cancer cells byinhibiting a PLK with the compound of any of claims 1 to 56 or thecomposition of claim 57.